@article{6f43310efb7b4244a91c5bd55951c15e,
title = "Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers",
abstract = "Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein.",
keywords = "1,6-hexanediol, C9orf72, amyloid-like polymers, cellular puncta not invested by surrounding membranes, intermediate filaments, labile, low complexity sequence polymers, toxic PRn and GRn poly-dipeptides",
author = "Yi Lin and Eiichiro Mori and Masato Kato and Siheng Xiang and Leeju Wu and Ilmin Kwon and McKnight, {Steven L.}",
note = "Funding Information: We thank Drs. Richard Losick, Ruth Lehmann, Deepak Nijhawan and Ting Han for valuable input; Dr. Robert Tycko of the National Institutes of Health for provision of Aβ-40 in the polymeric, prion state; Dr. Randal Halfmann of Stowers Institute for provision of sup35 in the polymeric, prion state; Drs. Joseph Ready and Hayden Ball for help in synthesis of the benzophenone-labeled PR 20 peptide; Drs. Anne Ephrussi and Denise Montell for communication of unpublished observations concerning their co-discovery of a spliced variant of Drosophila melanogaster tropomyosin having intermediate filament-like properties; Dr. Luke Rice for provision of pocine brain tubulin; the Live Cell Imaging and Electron Microscopy Core Laboratories at UTSWMC for technical assistance; and the Nijhawan laboratory at UTSWMC for technical advice and access to equipment for preparing cryo-mill-generated cellular lysates. This work was supported by the National Research Foundation of Korea (NRF) grants (#2016R1C1B2008776 and #2016R1A4A1011189) awarded IK by the Korean government, grant #5UO1-GM107623-02 awarded SLM from the National Institute of General Medical Sciences, and unrestricted funds provided to SLM by an anonymous donor. Publisher Copyright: {\textcopyright} 2016",
year = "2016",
month = oct,
day = "20",
doi = "10.1016/j.cell.2016.10.003",
language = "English (US)",
volume = "167",
pages = "789--802.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}